tbuckley/cabot-search huggingface dataset:
ROCK inhibition enhanced hepatocyte liver engraftment by retaining membrane CD59 and attenuating complement activation
Authors: Haoxin Ma, Chao Wang, Shulong Liang, Xinlu Yu, Yuan Yuan, Zhuanman Lv, Jiqianzhu Zhang, Caixia Jin, Jiangbo Zhu, Chao Wang, Pingxin Sun, Wenlin Li
Journal: Molecular Therapy (2023)

Hepatocyte transplantation can be an effective treatment for patients with certain liver-based metabolic disorders and liver injuries. Hepatocytes are usually infused into the portal vein, from which hepatocytes migrate into the liver and integrate into the liver parenchyma. However, early cell loss and poor liver engraftment represent major hurdles to sustaining the recovery of diseased livers after transplantation. In the present study, we found that ROCK (Rho-associated kinase) inhibitors significantly enhanced in vivo hepatocyte engraftment. Mechanistic studies suggested that the isolation of hepatocytes caused substantial degradation of cell membrane proteins, including the complement inhibitor CD59, probably due to shear stress-induced endocytosis. ROCK inhibition by ripasudil, a clinically used ROCK inhibitor, can protect transplanted hepatocytes by retaining cell membrane CD59 and blocking the formation of the membrane attack complex. Knockdown of CD59 in hepatocytes eliminates ROCK inhibition-enhanced hepatocyte engraftment. Ripasudil can accelerate liver repopulation of fumarylacetoacetate hydrolase-deficient mice. Our work reveals a mechanism underlying hepatocyte loss after transplantation and provides immediate strategies to enhance hepatocyte engraftment by inhibiting ROCK. Hepatocyte transplantation can be an effective treatment for patients with certain liver-based metabolic disorders and liver injuries. Hepatocytes are usually infused into the portal vein, from which hepatocytes migrate into the liver and integrate into the liver parenchyma. However, early cell loss and poor liver engraftment represent major hurdles to sustaining the recovery of diseased livers after transplantation. In the present study, we found that ROCK (Rho-associated kinase) inhibitors significantly enhanced in vivo hepatocyte engraftment. Mechanistic studies suggested that the isolation of hepatocytes caused substantial degradation of cell membrane proteins, including the complement inhibitor CD59, probably due to shear stress-induced endocytosis. ROCK inhibition by ripasudil, a clinically used ROCK inhibitor, can protect transplanted hepatocytes by retaining cell membrane CD59 and blocking the formation of the membrane attack complex. Knockdown of CD59 in hepatocytes eliminates ROCK inhibition-enhanced hepatocyte engraftment. Ripasudil can accelerate liver repopulation of fumarylacetoacetate hydrolase-deficient mice. Our work reveals a mechanism underlying hepatocyte loss after transplantation and provides immediate strategies to enhance hepatocyte engraftment by inhibiting ROCK.
In Humanized Sickle Cell Mice, Imatinib Protects Against Sickle Cell–Related Injury
Authors: Enrica Federti, Alessandro Matte, Antonio Recchiuti, Francesca Garello, Alessandra Ghigo, Wassim El Nemer, Enzo Terreno, Angela Amoresano, Domenico Mattoscio, Franco Turrini, Christophe Lebouef, Anne Janin, Antonella Pantaleo, Roberta Russo, Mickael Marin, Iana Iatcencko, Veronica Riccardi, Angela Siciliano, Achille Iolascon, Carlo Brugnara, Lucia De Franceschi
Journal: HemaSphere (2023)

Drug repurposing is a valuable strategy for rare diseases. Sickle cell disease (SCD) is a rare hereditary hemolytic anemia accompanied by acute and chronic painful episodes, most often in the context of vaso-occlusive crisis (VOC). Although progress in the knowledge of pathophysiology of SCD have allowed the development of new therapeutic options, a large fraction of patients still exhibits unmet therapeutic needs, with persistence of VOCs and chronic disease progression. Here, we show that imatinib, an oral tyrosine kinase inhibitor developed for the treatment of chronic myelogenous leukemia, acts as multimodal therapy targeting signal transduction pathways involved in the pathogenesis of both anemia and inflammatory vasculopathy of humanized murine model for SCD. In addition, imatinib inhibits the platelet-derived growth factor-B–dependent pathway, interfering with the profibrotic response to hypoxia/reperfusion injury, used to mimic acute VOCs. Our data indicate that imatinib might be considered as possible new therapeutic tool for chronic treatment of SCD.
Modern Day Approach to Extraesophageal Reflux: Clearing the Murky Lens
Authors: Rena Yadlapati, Walter W. Chan
Journal: Clinical Gastroenterology and Hepatology (2023)

Airway symptoms are often regarded as extraesophageal syndromes of gastroesophageal reflux. Although an increasingly prevalent reason for referral to gastroenterologists, extraesophageal presentations remain among the most challenging and frustrating. With clinical guidance or recommendations often leaning on low levels of evidence, or lack thereof, and expert opinions, the paradigm of extraesophageal reflux (EER) remains under scrutiny and viewed through a murky lens. Adding to the confusion is the cross-disciplinary nature, with other specialty stakeholders, such as otolaryngologists, who may have different priorities and approaches. In this commentary, we clear the lens on EER by acknowledging important updates in clinical guidance, highlighting areas ripe for research inquiry, and presenting a perspective on the future paradigm of EER (Table 1). Table 1Priority Areas for Future Investigation in EER Knowledge gaps in diagnosis of EER Clinical value of upper GI endoscopy Optimal ambulatory reflux monitoring testing modality Whether day to day variability in EER physiology exists Significance of nonacidic or weakly acidic reflux Whether focus should remain on distal esophageal reflux or proximal reflux Diagnostic thresholds of reflux monitoring to use for EER Cost-effectiveness of upfront testing across all patients evaluated for EER Whether noninvasive screening methods can reliably stratify risk of EER Value of biochemical testing Priority research areas for EER management Low-acid or other targeted dietary approaches Psychological/behavioral interventions Multidisciplinary consensus-based management strategy Personalized phenotype-based management approach EER, extraesophageal reflux; GI, gastrointestinal. Open table in a new tab EER, extraesophageal reflux; GI, gastrointestinal.
AIGAN: Attention–encoding Integrated Generative Adversarial Network for the reconstruction of low-dose CT and low-dose PET images
Authors: Yu Fu, Shunjie Dong, Meng Niu, Le Xue, Hanning Guo, Yanyan Huang, Yuanfan Xu, Tianbai Yu, Kuangyu Shi, Qianqian Yang, Yiyu Shi, Hong Zhang, Mei Tian, Cheng Zhuo
Journal: Medical Image Analysis (2023)
Berberine improves central memory formation of CD8+ T cells: Implications for design of natural product-based vaccines
Authors: Mingyan Li, Yaling Wang, Lingzhi Zhang, Changxing Gao, Jing J. Li, Jiandong Jiang, Qing Zhu
Journal: Acta Pharmaceutica Sinica B (2023)

Berberine (BBR) as one of the most effective natural products has been increasingly used to treat various chronic diseases due to its immunosuppressive/tolerogenic activities. However, it is unknown if BBR can be applied without abrogating the efforts of vaccination. Here we show that priming of CD8+ T cells in the presence of BBR lead to improved central memory formation (Tcm) with substantially reduced effector proliferation, primarily orchestrated through activation of AMPK and Stat5. Tcm derived from vaccinated mice fed with BBR were able to adoptively transfer protective immunity to naïve recipients. Vaccination of BBR-fed mice conferred better memory protection against infection without losing immediate effector efficacy, suggesting appreciable benefits from using BBR in vaccination. Thus, our study may help to lay the groundwork for mechanistic understanding of the immunomodulatory effects of natural products and their potential use as adjuvant that allows the design of novel vaccines with more desirable properties.
Single nuclei transcriptomics delineates complex immune and kidney cell interactions contributing to kidney allograft fibrosis
Authors: Jennifer M. McDaniels, Amol C. Shetty, Cem Kuscu, Canan Kuscu, Elissa Bardhi, Thomas Rousselle, Cinthia Drachenberg, Manish Talwar, James D. Eason, Thangamani Muthukumar, Daniel G. Maluf, Valeria R. Mas
Journal: Kidney International (2023)
Multi-organ single-cell analysis reveals an on/off switch system with potential for personalized treatment of immunological diseases
Authors: Sandra Lilja, Xinxiu Li, Martin Smelik, Eun Jung Lee, Joseph Loscalzo, Pratheek Bellur Marthanda, Lang Hu, Mattias Magnusson, Oleg Sysoev, Huan Zhang, Yelin Zhao, Christopher Sjöwall, Danuta Gawel, Hui Wang, Mikael Benson
Journal: Cell Reports Medicine (2023)

Prioritization of disease mechanisms, biomarkers, and drug targets in immune-mediated inflammatory diseases (IMIDs) is complicated by altered interactions between thousands of genes. Our multi-organ single-cell RNA sequencing of a mouse IMID model, namely collagen-induced arthritis, shows highly complex and heterogeneous expression changes in all analyzed organs, even though only joints showed signs of inflammation. We organized those into a multi-organ multicellular disease model, which shows predicted molecular interactions within and between organs. That model supports that inflammation is switched on or off by altered balance between pro- and anti-inflammatory upstream regulators (URs) and downstream pathways. Meta-analyses of human IMIDs show a similar, but graded, on/off switch system. This system has the potential to prioritize, diagnose, and treat optimal combinations of URs on the levels of IMIDs, subgroups, and individual patients. That potential is supported by UR analyses in more than 600 sera from patients with systemic lupus erythematosus.
Learning from the COVID-19 pandemic response to strengthen undocumented migrant-sensitive health systems: case studies from four countries
Authors: Eleonora Genovese, Kathleen R. Page, Johann Cailhol, Yves Jackson
Journal: The Lancet Regional Health - Europe (2023)

Undocumented migrants are a vulnerable population group in the context of the COVID-19 pandemic due to increased risk of infection, severe morbidity, and mortality. In this Personal View, we analyze the COVID-19 pandemic responses, particularly vaccination campaigns, vis à vis undocumented migrants, and discuss lessons learned. Our empirical observations as clinicians and public health practitioners in Italy, Switzerland, France, and the United States are supplemented by a literature review, and presented through country case studies focusing on Governance, Service Delivery, and Information. We propose recommendations to capitalize on the COVID-19 pandemic response as an entry point to strengthen migrant-sensitive provisions into health system frameworks, by: providing specific guidance in health policies and plans; developing tailored implementation approaches with outreach and mobile services, with translated and socio-culturally adapted information, and engagement of migrant communities and third sector actors; and developing systematic monitoring & evaluation systems with disaggregated migrant data from National Health Service and third sector providers.
Refining epigenetic prediction of chronological and biological age
Authors: Elena Bernabeu, Daniel L. McCartney, Danni A. Gadd, Robert F. Hillary, Ake T. Lu, Lee Murphy, Nicola Wrobel, Archie Campbell, Sarah E. Harris, David Liewald, Caroline Hayward, Cathie Sudlow, Simon R. Cox, Kathryn L. Evans, Steve Horvath, Andrew M. McIntosh, Matthew R. Robinson, Catalina A. Vallejos, Riccardo E. Marioni
Journal: Genome Medicine (2023)

Abstract Background Epigenetic clocks can track both chronological age (cAge) and biological age (bAge). The latter is typically defined by physiological biomarkers and risk of adverse health outcomes, including all-cause mortality. As cohort sample sizes increase, estimates of cAge and bAge become more precise. Here, we aim to develop accurate epigenetic predictors of cAge and bAge, whilst improving our understanding of their epigenomic architecture. Methods First, we perform large-scale ( N = 18,413) epigenome-wide association studies (EWAS) of chronological age and all-cause mortality. Next, to create a cAge predictor, we use methylation data from 24,674 participants from the Generation Scotland study, the Lothian Birth Cohorts (LBC) of 1921 and 1936, and 8 other cohorts with publicly available data. In addition, we train a predictor of time to all-cause mortality as a proxy for bAge using the Generation Scotland cohort (1214 observed deaths). For this purpose, we use epigenetic surrogates (EpiScores) for 109 plasma proteins and the 8 component parts of GrimAge, one of the current best epigenetic predictors of survival. We test this bAge predictor in four external cohorts (LBC1921, LBC1936, the Framingham Heart Study and the Women’s Health Initiative study). Results Through the inclusion of linear and non-linear age-CpG associations from the EWAS, feature pre-selection in advance of elastic net regression, and a leave-one-cohort-out (LOCO) cross-validation framework, we obtain cAge prediction with a median absolute error equal to 2.3 years. Our bAge predictor was found to slightly outperform GrimAge in terms of the strength of its association to survival (HR GrimAge = 1.47 [1.40, 1.54] with p = 1.08 × 10 −52 , and HR bAge = 1.52 [1.44, 1.59] with p = 2.20 × 10 −60 ). Finally, we introduce MethylBrowsR, an online tool to visualise epigenome-wide CpG-age associations. Conclusions The integration of multiple large datasets, EpiScores, non-linear DNAm effects, and new approaches to feature selection has facilitated improvements to the blood-based epigenetic prediction of biological and chronological age.
Gene-by-environment interactions are pervasive among natural genetic variants
Authors: Shi-An A. Chen, Alexander F. Kern, Roy Moh Lik Ang, Yihua Xie, Hunter B. Fraser
Journal: Cell Genomics (2023)

Gene-by-environment (GxE) interactions, in which a genetic variant's phenotypic effect is condition specific, are fundamental for understanding fitness landscapes and evolution but have been difficult to identify at the single-nucleotide level. Although many condition-specific quantitative trait loci (QTLs) have been mapped, these typically contain numerous inconsequential variants in linkage, precluding understanding of the causal GxE variants. Here, we introduce BARcoded Cas9 retron precise parallel editing via homology (CRISPEY-BAR), a high-throughput precision genome editing strategy, and use it to map GxE interactions of naturally occurring genetic polymorphisms impacting yeast growth. We identified hundreds of GxE variants within condition-specific QTLs, revealing unexpected genetic complexity. Moreover, we found that 93.7% of non-neutral natural variants within ergosterol biosynthesis pathway genes showed GxE interactions, including many impacting antifungal drug resistance through diverse molecular mechanisms. In sum, our results suggest an extremely complex, context-dependent fitness landscape characterized by pervasive GxE interactions while also demonstrating massively parallel genome editing as an effective means for investigating this complexity.
Extraordinary selection on the human X chromosome associated with archaic admixture
Authors: Laurits Skov, Moisès Coll Macià, Elise Anne Lucotte, Maria Izabel Alves Cavassim, David Castellano, Mikkel Heide Schierup, Kasper Munch
Journal: Cell Genomics (2023)

The X chromosome in non-African humans shows less diversity and less Neanderthal introgression than expected from neutral evolution. Analyzing 162 human male X chromosomes worldwide, we identified fourteen chromosomal regions where nearly identical haplotypes spanning several hundred kilobases are found at high frequencies in non-Africans. Genetic drift alone cannot explain the existence of these haplotypes, which must have been associated with strong positive selection in partial selective sweeps. Moreover, the swept haplotypes are entirely devoid of archaic ancestry as opposed to the non-swept haplotypes in the same genomic regions. The ancient Ust'-Ishim male dated at 45,000 before the present (BP) also carries the swept haplotypes, implying that selection on the haplotypes must have occurred between 45,000 and 55,000 years ago. Finally, we find that the chromosomal positions of sweeps overlap previously reported hotspots of selective sweeps in great ape evolution, suggesting a mechanism of selection unique to X chromosomes.
Osimertinib treatment based on plasma T790M monitoring in patients with EGFR-mutant non-small-cell lung cancer (NSCLC): EORTC Lung Cancer Group 1613 APPLE phase II randomized clinical trial
Authors: J. Remon, B. Besse, S. Ponce Aix, A. Callejo, K. Al-Rabi, R. Bernabe, L. Greillier, M. Majem, N. Reguart, I. Monnet, S. Cousin, P. Garrido, G. Robinet, R. Garcia Campelo, A. Madroszyk, J. Mazières, H. Curcio, B. Wasąg, Y. Pretzenbacher, B. Fournier, A.-M.C. Dingemans, R. Dziadziuszko
Journal: Annals of Oncology (2023)
Nimbolide targeting SIRT1 mitigates intervertebral disc degeneration by reprogramming cholesterol metabolism and inhibiting inflammatory signaling
Authors: Yun Teng, Yixue Huang, Hao Yu, Cenhao Wu, Qi Yan, Yingjie Wang, Ming Yang, Haifeng Xie, Tianyi Wu, Huilin Yang, Jun Zou
Journal: Acta Pharmaceutica Sinica B (2023)

Inflammation, abnormal cholesterol metabolism, and macrophage infiltration are involved in the destruction of the extracellular matrix of the nucleus pulposus (NP), culminating in intervertebral disc degeneration (IDD). Whether nimbolide (Nim), a natural extract, can alleviate IDD is unclear. In this study, we demonstrated that Nim promotes cholesterol efflux and inhibits the activation of the nuclear factor kappa B (NF-κB) and mitogen-activated protein kinase (MAPK) signaling pathways by activating sirtuin 1 (SIRT1) in nucleus pulposus cells (NPCs) during inflammation. Thus, Nim balanced matrix anabolism and catabolism of NPCs. However, the inhibition of SIRT1 significantly attenuated the effects of Nim. We also found that Nim promoted the expression of SIRT1 in RAW 264.7, which enhanced the proportion of M2 macrophages by facilitating cholesterol homeostasis reprogramming and impeded M1-like macrophages polarization by blocking the activation of inflammatory signaling. Based on these results, Nim can improve the microenvironment and facilitate matrix metabolism equilibrium in NPCs. Furthermore, in vivo treatment with Nim delayed IDD progression by boosting SIRT1 expression, modulating macrophage polarization and preserving the extracellular matrix. In conclusion, Nim may represent a novel therapeutic strategy for treating IDD.
Novel evidence that the ABO blood group shapes erythropoiesis and results in higher hematocrit for blood group B carriers
Authors: Romy Kronstein-Wiedemann, Sarah Blecher, Madeleine Teichert, Laura Schmidt, Jessica Thiel, Markus M. Müller, Jörn Lausen, Richard Schäfer, Torsten Tonn
Journal: Leukemia (2023)

The ABO blood group (BG) system is of great importance for blood transfusion and organ transplantation. Since the same transcription factors (TFs) and microRNAs (miRNAs) govern the expression of ABO BG antigens and regulate erythropoiesis, we hypothesized functional connections between both processes. We found significantly higher hemoglobin and hematocrit values in BG B blood donors compared to BG A. Furthermore, we observed that erythropoiesis in BG B hematopoietic stem/progenitor cells (HSPCs) was accelerated compared to BG A HSPCs. Specifically, BG B HSPCs yielded more lineage-specific progenitors in a shorter time (B: 31.3 ± 2.2% vs. A: 22.5 ± 3.0%). Moreover, non-BG A individuals exhibited more terminally differentiated RBCs with higher enucleation rates containing more hemoglobin compared to BG A. Additionally, we detected increased levels of miRNA-215-5p and -182-5p and decreased expression of their target TFs RUNX1 and HES-1 mRNAs in erythroid BG B precursor cells compared to BG A. This highlights the important roles of these factors for the disappearance of differentiation-specific glycan antigens and the appearance of cancer-specific glycan antigens. Our work contributes to a deeper understanding of erythropoiesis gene regulatory networks and identifies its interference with BG-specific gene expression regulations particularly in diseases, where ABO BGs determine treatment susceptibility and disease progression.
The opportunity for greater patient and public involvement and engagement in drug development and regulation
Authors: Olalekan Lee Aiyegbusi, Samantha Cruz Rivera, Kathy Oliver, Elaine Manna, Phil Collis, Bellinda L. King-Kallimanis, Vishal Bhatnagar, Ralf Herold, Jon Hopkins, Lisa Campbell, Alysha Croker, Myles Leach, Melanie J. Calvert
Journal: Nature Reviews Drug Discovery (2023)
Spatial multi-omics revealed the impact of tumor ecosystem heterogeneity on immunotherapy efficacy in patients with advanced non-small cell lung cancer treated with bispecific antibody
Authors: Xinyu Song, Anwen Xiong, Fengying Wu, Xuefei Li, Jing Wang, Tao Jiang, Peixin Chen, Xiaoshen Zhang, Zhikai Zhao, Huifang Liu, Lei Cheng, Chao Zhao, Zhehai Wang, Chaohu Pan, Xiaoli Cui, Ting Xu, Haitao Luo, Caicun Zhou
Journal: Journal for ImmunoTherapy of Cancer (2023)

Immunotherapy for malignant tumors has made great progress, but many patients do not benefit from it. The complex intratumoral heterogeneity (ITH) hindered the in-depth exploration of immunotherapy. Conventional bulk sequencing has masked intratumor complexity, preventing a more detailed discovery of the impact of ITH on treatment efficacy. Hence, we initiated this study to explore ITH at the multi-omics spatial level and to seek prognostic biomarkers of immunotherapy efficacy considering the presence of ITH.
Research advances in peptide‒drug conjugates
Authors: Liming Gong, Heming Zhao, Yanhong Liu, Hao Wu, Chao Liu, Shuangyan Chang, Liqing Chen, Mingji Jin, Qiming Wang, Zhonggao Gao, Wei Huang
Journal: Acta Pharmaceutica Sinica B (2023)

Peptide‒drug conjugates (PDCs) are drug delivery systems consisting of a drug covalently coupled to a multifunctional peptide via a cleavable linker. As an emerging prodrug strategy, PDCs not only preserve the function and bioactivity of the peptides but also release the drugs responsively with the cleavable property of the linkers. Given the ability to significantly improve the circulation stability and targeting of drugs in vivo and reduce the toxic side effects of drugs, PDCs have already been extensively applied in drug delivery. Herein, we review the types and mechanisms of peptides, linkers and drugs used to construct PDCs, and summarize the clinical applications and challenges of PDC drugs.
Abstract 2914: Serum Uric Acid is a Powerful Predictor of Survival in Patients With Stable Chronic Heart Failure Receiving Beta-Blocker Therapy
Authors: Pascal De Groote, Frederic Mouquet, Nicolas Lamblin, Joel Dagorn, Thierry Le Tourneau, Olivier Hennebert, Christophe Bauters
Journal: Circulation (2007)

Background: Previous studies have demonstrated that uric acid was a powerful predictor of survival in pts with chronic heart failure (CHF), but these studies were performed before the beta-blocker ...